2-amino-1-(2&#39;-bromo-3&#39;-substituted phenyl) pyridinium compounds

ABSTRACT

Compounds of the formula ##STR1## exhibit central nervous system stimulating properties and act as muscle relaxants.

This is a division of application Ser. No. 532,796, filed Dec. 16, 1974which is a division of Ser. No. 382,804, filed July 26, 1973 now U.S.Pat. No. 3,868,374.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide new compounds havingcentral nervous system (CNS) stimulating activity. Another object is toprovide new compounds having muscle relaxant properties. A furtherobject is to provide intermediates for the preparation of the finalcompounds of the invention. Yet another object is to provide a methodfor the preparation of both the intermediate and the final compounds ofthe present invention. Still another object is to provide a method forthe administration of the final compounds of the invention. A stillfurther object is to provide pharmaceutical compositions containing asactive ingredients the final compounds of the present invention. Theseand other objects of the present invention will be apparent from thefollowing description.

SUMMARY OF THE INVENTION

The compounds of the present invention have the following formula##STR2## wherein m may be 1 or 2; when m is 1, R occupies either the4-or 5- positions of the original 2-aminopyrimidine, but when R ishalogen, it occupies only position-5; when m is 2, the twoR-substituents occupy the 4- and 5-positions of the original2-aminopyrimidine, but only one of the two R-substituents can be halogenand it must occupy the 5-position;

R may be the same or different and may be hydrogen, halogen (F, Cl, orBr), alkyl of from 1 to 4 carbons, benzyl, phenyl, or mono-substitutedphenyl wherein the substituent may be halogen (F, Cl, Br or I), alkyl offrom 1 to 4 carbons, alkoxy of from 1 to 4 carbons, or trifluoromethyl;

R' may be hydrogen, halogen (F, Cl, Br or I), alkyl of from 1 to 4carbons, alkoxy of from 1 to 4 carbons, alkylthio of from 1 to 4carbons, alkylsulfonyl wherein the alkyl radical has from 1 to 4carbons, phenyl, phenyloxy, sulfamoyl, dialkylamidosulfonyl wherein eachalkyl radical may have from 1 to 4 carbons, trifluoromethyl,mono-substituted phenyl or mono-substituted phenyloxy wherein thesubstituent may be halogen (F, Cl, Br or I), alkyl of from 1 to 4carbons, alkoxy of from 1 to 4 carbons or trifluoromethyl; n is 2 or 3,and pharmaceutically acceptable acid addition salts thereof.

The foregoing compounds possess central nervous system stimulatingproperties and act as muscle relaxants.

DETAILED DESCRIPTION

The final compound I of the present invention may be prepared byreacting a 2-aminopyrimidine II with an o-bromophenalkylene bromide III.This reaction takes place in any solvent or solvent mixture in which thereactants can be dissolved and which has a boiling point of at leastabout 100° C. Typical solvents are aromatic hydrocarbons, ethers,aliphatic alcohols or aryl-substituted aliphatic alcohols. Toluene andxylene are examples of suitable aromatic hydrocarbons. Monomethyl etherof diethylene glycol, dimethyl ether of diethylene glycol (diglyme),monomethyl ether of ethylene glycol or dimethyl ether of ethylene glycol(glyme) are examples of suitable ethers. n-Amyl alcohol is an example ofa suitable aliphatic alcohol, while benzyl alcohol is an example of asuitable aryl-substituted aliphatic alcohol. Heating compounds II andIII in a solvent as described above, or a mixture thereof, attemperatures from about 100° to about 140° C for a period of severalhours, typically from about 3 to about 24 hours produces a pyrimidiniumcompound IV. The latter is converted to an imino compound V by treatingwith a water miscible alcohol and an alkali metal alkoxide of up to 3carbon atoms. The reaction takes place at room temperature over a periodof from about 1 to about 4 hours. Compound V may be converted to thefinal compound I by treating with a water miscible alcohol and an alkalimetal alkoxide of up to 3 carbons in the presence of copper at atemperature of from about 60° to about 120° for several days, typicallyfrom about 4 to about 10 days. Alternatively, IV may be converteddirectly to I by heating at a temperature of from about 60° C to about120° C for about 4 to 10 days, typically from about 6 to about 8 days inthe presence of potassium carbonate and copper in a solvent such asdimethylformamide, dimethylacetamide, dichlorobenzene, trichlorobenzene,or diethylbenzene. Preferably, however, IV may be converted directly toI by heating at a temperature of from about 60° to about 120° C forabout 4 to 10 days, typically from about 6 to about 8 days in thepresence of an alkali metal hydroxide, alkali metal carbonate,tris-alkali metal phosphate, alkali metal metaborate or alkali metaltetraborate in a solvent comprising a mixture of water and a watermiscible alcohol in the presence of copper. Specific examples ofsuitable compounds include LiOH, NaOH, KOH, RbOH, CsOH, Na₂ CO₃, K₂ CO₃,Rb₂ CO₃, Cs₂ CO₃, Na₃ PO₄, K₃ PO₄, Rb₃ PO₄, Cs₃ PO₄, Na₂ B₂ O₄, Na₂ B₄O₇, K₂ B₂ O₄, and K₂ B₄ O₇. The ratios of water and alcohol in themixture of water and a water miscible alcohol are such that ahomogeneous single phase system results.

When m is 1, and when R occupies only the 5-position of II and R'occupies only the 5-position (para to the bromine atom) of III, only oneisomer, I, is formed. When m is 1, and when R occupies only the4-position of IIa, and R' occupies only the 5-position of III, twoisomers, Ia and Ib are formed via the intermediates IVa or Va and IVband Vb, respectively. When m is 2, and since the two R's occupy only the4-, 5-positions and R' occupies only the 5-position of III, two isomericproducts, Ia and Ib are formed. These isomers, in all instances, can beseparated by conventional procedures, e.g., fractional recrystallizationor column chromatography.

The foregoing reaction sequence is illustrated by the followingequations: ##STR3##

The intermediates of formula III wherein n is 2 may be prepared bytreating an o-bromobenzyl alcohol VI with PBr₃ at temperatures of fromabout 0° to about 100° C for a period of from about 1 to about 6 hours.The resulting o-bromobenzyl bromide VII is then treated with sodiumcyanide in the presence of water and a water miscible alcohol to yieldan o-bromophenylacetonitrile VIII. Treatment of the latter with analcohol in the presence of concentrated sulfuric acid yields thecorresponding ester IX. Treatment of the latter with lithium aluminumhydride yields an o-bromophenethanol. Treatment of the latter with PBr₃at temperatures within the range of from about 0° to about 100° for aperiod of from about 1 to 6 hours yields the correspondingo-bromophenethyl bromide XI. The foregoing reaction sequence isillustrated by the following equations ##STR4##

The intermediates of formula III wherein n is 3 may be prepared bytreating a compound of formula XI with sodium cyanide in the presence ofwater and a water miscible alcohol to yield ano-bromophenylpropionitrile XII. Treatment of the latter with an alcoholin the presence of concentrated sulfuric acid yields the correspondingester XIII. Treatment of the latter with lithium aluminum hydride yieldsan o-bromophenpropanol. Treatment of the latter with PBr₃ attemperatures within the range of from about 0° to about 100° C for aperiod of from about 1 to about 6 hours yields the correspondingo-bromophenpropyl bromide XV. The foregoing reaction sequence isillustrated by the following equations ##STR5##

When R' is alkylthio the compounds of formula XI or XV may be preparedby nitrating an o-bromobenzyl alcohol XVI at 0° C using a mixture ofnitric and sulfuric acids. The resulting isomeric mixture of nitrated2-bromobenzyl alcohols is separated by conventional techniques. Eachseparated isomer XVII may then be reduced to the corresponding amineXVIII by means of zinc and hydrochloric acid. Treatment of the aminoderivative XVIII with nitrous acid and then with sodium alkylmercaptideyields the corresponding alkylthio-2-bromobenzyl alcohol XIX. ##STR6##

Treatment of the compound of formula XIX with PBr₃ as shown in thesequence proceeding from X to XI, and from XIV to XV yields the compoundof formula XI or XV wherein R' is alkylthio.

When R' is trifluoromethyl, the intermediate of formula VII may beprepared by reacting a trifluoromethylphenyl magnesium bromide XX withmethyl iodide to obtain a trifluoromethyl toluene XXI. Treatment of thelatter with bromine in the presence of iron powder at 20° C yields abromo-substituted trifluoromethyl toluene XXII. Treatment of the latterwith bromine in the presence of light and a peroxide catalyst yields thecorresponding bromo-trifluoromethylbenzyl bromide XXIII. ##STR7##

Compounds of formula III wherein R' is phenyl, halogen-substitutedphenyl, alkyl-substituted phenyl, alkoxy-substituted phenyl, ortrifluoromethyl-substituted phenyl may be prepared by treating anamino-substituted o-bromobenzoic acid XXVIII with acetic anhydride andthen with nitrous acid. The resultingN-acetamido-N-nitroso-o-bromobenzoic acid XXIX is then treated withbenzene or an R-substituted benzene wherein R is halogen, alkyl, alkoxyor trifluoromethyl according to the procedure of Haworth et al, supra.The aryl-substituted o-bromobenzoic acid is then treated with LiAlH₄ orAlH₃ according to known techniques to yield the correspondingaryl-substituted o-bromobenzyl alcohol XXXI. The reaction sequence is asfollows: ##STR8##

The compounds of the present invention may be administered to mammalianspecies as central nervous system stimulants and as muscle relaxants. Inthe rat, responses to the stimulant activity of the compounds of thepresent invention include increased activity and body tremors. Themuscle relaxant properties manifest themselves by responses that includedecreased limb tone, decreased grip strength, and limb paralysis. Inboth the stimulant and muscle relaxant activities, the onset of activityis rapid, i.e., within about 15 minutes; the activity persists for about2 hours or longer. In the rat the dosage range varies from about 6.25 toabout 50 mg/kg for both activities, while in humans the dosage rangevaries from about 40 to about 2000 mg. daily in about four divided dosesfor both activities.

In addition to serving as intermediates for the preparation of compoundsof formula I, the pyrimidinium compounds of formula IV are themselveseffective bactericides.

Microbial bioassays, as described in "The Microbial World," by R. Y.Stanier, M. Doudoroff and E. A. Adelberg, Prentice-Hall, Inc., EnglewoodCliffs, N.J., 3rd Ed., p. 858, are employed to determine thebactericidal properties of the pyrimidinium compounds IV of thisinvention. The bacteria employed include Staphylococcus aureus, 1,Streptococcus pyogenes, 2, Salmonella schottmuelleri, 3, Salmonellagallinarum, 4, Pseudomonas aeruginosa, 5, Proteus vulgaris, 6,Escherichia coli, 7, Pasturella multocida, 8, and Mycobacteriumtuberculosis, 9.

In the procedure, a sterile agar plate is seeded with the test organism,and then a number of glass cylinders are placed on its surface, forminga series of little cups. A known dilution of the compounds of thisinvention is added to each cup and the entire plate is then incubateduntil significant bacterial growth has occurred. The compounds of thisinvention diffuse out of the cup into the surrounding agar and produce azone of inhibition. In this fashion it is possible to find the minimuminhibiting concentration (mic), of the compound that produces arecognizable zone of inhibition. The following summarizes the data.

    __________________________________________________________________________            mic of Compound, Micrograms, (mcg)/ml                                         Compound                                                                             Compound                                                                             Compound                                                                             Compound                                                 of Ex. 3,                                                                            of Ex. 10,                                                                           of Ex. 12,                                                                           of Ex. 16                                        Microorganism                                                                         col. 3 col. 3 col. 3 col. 3                                           __________________________________________________________________________    1       12.5   6.25   6.25   3.13                                             2       50.0   50.0   25.0   12.5                                             3       50.0   12.5   12.5   12.5                                             4       25.0   12.5   12.5   6.25                                             5       25.0   25.0   25.0   12.5                                             6       25.0   25.0   25.0   12.5                                             7       25.0   12.5   6.25   3.13                                             8       12.5   25.0   12.5   6.25                                             9       6.25   1.57   0.78   0.39                                             __________________________________________________________________________

The compounds of the present invention in the described dosages may beadministered orally; however, other routes such as intraperitoneally,subcutaneously, intramuscularly or intravenously may be employed.

The active compounds of the present invention are orally administered,for example, with an inert diluent or with an assimilable ediblecarrier, or they may be enclosed in hard or soft gelatin capsules, orthey may be compressed into tablets, or they may be incorporateddirectly with the food of the diet. For oral therapeutic administration,the active compounds of this invention may be incorporated withexcipients and used in the form of tablets, troches, capsules, elixirs,suspensions, syrups, wafers, chewing gum, and the like. Suchcompositions and preparations should contain at least 0.1% of activecompound. The percentage in the compositions and preparations may, ofcourse, be varied and may conveniently be between about 5% to about 75%or more of the weight of the unit. The amount of active compound in suchtherapeutically useful compositions or preparations is such that asuitable dosage will be obtained. Preferred compositions or preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between about 10 and 200 milligrams of activecompound.

The tablets, troches, pills, capsules and the like may also contain thefollowing: a binder such as gum tragacanth, acacia, corn starch orgelatin; an excipient such as dicalcium phosphate; a disintegratingagent such as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain in addition to materials of theabove type a liquid carrier such as a fatty oil. Various other materialsmay be present as coatings or to otherwise modify the physical form ofthe dosage unit, for instance, tablets, pills or capsules may be coatedwith shellac, sugar or both. A syrup or elixir may contain the activecompounds, sucrose as a sweetening agent, methyl and propyl parabens aspreservatives, a dye and a flavoring such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage unit form should bepharmaceutically pure and substantially nontoxic in the amountsemployed.

As to the pharmaceutically acceptable salts, those coming within thepurview of the invention include the pharmaceutically acceptableacid-addition salts. Acids useful for preparing these acid-additionsalts include, inter alia, inorganic acids, such as the hydrohalic acids(e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid,and phosphoric acid, and inorganic acids such as maleic, fumaric,tartaric, citric, acetic, benzoic, 2-acetoxybenzoic, salicylic, succinicacid, theophylline, 8-chlorotheophylline, p-aminobenzoic,p-acetamidobenzoic, or methanesulfonic.

The following examples illustrate the following invention without,however, limiting the same thereto. All temperatures are expressed indegrees Centigrade.

EXAMPLE 1 11,12-Dihydropyrimido[2,1-b][1,3]benzodiazepine A.o-Bromobenzyl Bromide

To 187.0 g of o-bromobenzyl alcohol at room temperature, with stirring,is added dropwise, 271.0 g of phosphorus tribromide. After the additionis complete, stirring is continued for three hours at room temperature.The mixture is then heated at 90°-100° for 3 hours and poured into 6 kgof crushed ice. The hydrolysis mixture is extracted with three 600 mlportions of ether, the ether extracts are washed, dried, andconcentrated to give o-bromobenzyl bromide, bp. about 130°-132° (15mm).

B. o-Bromophenylacetonitrile

To a suspension of 220.0 g of sodium cyanide in 265 ml of water and 380ml of absolute ethanol, is added, while stirring, a solution of 911.0 gof o-bromobenzyl bromide in 911 ml of ethanol. The reaction proceedsexothermally, but is eventually heated under reflux for about 0.5 hour,then cooled in an ice-bath, and filtered. The solid is washed withether, the filtrate is concentrated, the residue is suspended in 300 mlof water and extracted with three 500 ml portions of ether. The etherextracts are washed, dried, and the solvent is removed. The residue isdistilled to give 730 g of the named product, bp 141°-142° (12mm).

C. Ethyl-o-bromophenylacetate

To a cooled solution of 730.0 g of o-bromophenylacetonitrile in 2.9 l ofabsolute ethanol is added, dropwise, while stirring, 740 ml ofconcentrated sulphuric acid. The addition requires about 2 hours. Thereaction mixture is heated under reflux for 9 hours, poured into icewater, and extracted with 2.5 l of ether. The ether extracts are washed,dried, and concentrated. The residue is distilled to give 780.0 g ofethyl o-bromophenylacetate, bp. about 115°-117° (4mm), n_(D) ²⁶ 1,5434.

D. o-Bromophenethyl alcohol

To a stirred suspension of 106.0 g of lithium aluminum hydride in 3.7 lof anhydrous ether, is added, dropwise, a solution of 780.0 g of ethylo-bromophenylacetate in 3.1 l of anhydrous ether. The reaction mixtureis stirred for about 3 hours and then heated under reflux for about 5hours. The mixture is cooled, then treated dropwise with 800 ml ofwater, and 1.5 l of 10% aqueous hydrochloric acid. The ether solution iswashed, dried, concentrated, and the residue is distilled to give 554.0g of o-bromophenethyl alcohol, bp. about 130°-132° (8mm), n_(D) ²⁰1,5760.

E. o-Bromophenethyl bromide

To 550.0 g of o-bromophenethyl alcohol, while stirring, is added,dropwise, 375.0 g of phosphorus tribromide. After stirring for 3 hoursat room temperature, the reaction mixture is heated on a steam bath for3 hours and then poured into 6 kg of crushed ice. The mixture isextracted with three 600 and two 200 ml portions of ether. The etherextracts are washed, dried, concentrated, and the residue is distilledto give 531.0 g of o-bromophenethyl bromide, bp. about 86°-88° (0.9mm),n_(D) ²⁶ 1.5922.

F. 2-Amino-1-(o-bromophenethyl) pyrimidinium Bromide

To a solution of 212.0 g of o-bromophenethyl bromide in 400 ml of dryxylene is added a solution of 121.0 g of 2-aminopyrimidine in 400 ml ofdry xylene. The mixture is heated under reflux for about 3 hours,cooled, and the xylene solution is decanted from the crystalline solid.The solid is triturated with 300 ml of 2-propanol, filtered, and driedto give 138.0 g of the product. The xylene solution is again heatedunder reflux for 16 hours and by the same procedure, an additional 43.0g of product is recovered. The total of about 181.0 g of product isrecrystallized from 2-propanol to give 170.0 g of the title compound,mp. about 231°-232°.

G. 11,12-Dihydropyrimido[2,1-b][1,3]benzodiazepine

To a solution of 9.0 g of 2-amino-1-(o-bromophenethyl)pyridinium bromidein 55 ml of dimethylformamide is added 10.3 g of micronized, anhydrouspotassium carbonate and 0.5 g of copper bronze. The mixture is heated at100° for about 7 days under nitrogen while stirring, and then isfiltered while hot. The filtrate is concentrated to dryness in vacuo togive about 8.6 g of residue. This is extracted with two 125 ml portionsof boiling diisopropyl ether. The diisopropyl ether solution is treatedwith Darco, filtered, and concentrated to about 40 ml to give oncooling, about 7.2 g of 11,12-dihydropyrimido[2,1-b][1,3]benzodiazepine,mp about 45°-46°.

EXAMPLE 212,13-Dihydro-2-methylthio-11H-pyrimido[2,1-b][1,3]benzodiazocine A.2-Bromo-5-methylthiobenzyl Bromide

2-Bromo-5-methylthiobenzyl alcohol is prepared by the following sequenceof reactions: 2-bromo-5-nitrobenzoic acid is reduced to2-bromo-5-aminobenzoic acid by means of iron and hydrochloric acid inaqueous ethanol. The 2-bromo-5-aminobenzoic acid is diazotized withsodium nitrite in aqueous sulfuric acid, and the diazonium compoundtreated with sodium methylmercaptide to give 2-bromo-5-methylthiobenzoicacid. The 2-bromo-5-methylthiobenzoic acid is converted to its methylester by heating under reflux with methanol-concentrated sulfuric acid,the methyl ester is isolated by ether extraction from the esterificationmixture, recovered from the ether solution, distilled for purification,and reduced with lithium aluminum hydride to yield2-bromo-5-methylthiobenzyl alcohol. Treatment of the preceding compoundwith PBr₃ as described in part A of example 1 gives2-bromo-5-methylthiobenzyl bromide.

B. 3-(2-Bromo-5-(methylthio)phenyl)-1-propanol

To a suspension of 25.0 g of magnesium ribbon in a solution of 0.5 g ofiodine in 550 ml of anhydrous ether is added 5 ml of a solution of 296.0g of 2-bromo-5-(methylthio)benzyl bromide in 250 ml of anhydrous ether.The reaction is initiated by gentle heating, and the remainder of thesolution is then added dropwise so as to maintain a reflux.Subsequently, the mixture is heated and stirred under reflux for 1 hour,and then cooled to 10°. A stream of nitrogen gas that has been bubbledthrough a reservoir containing 48.0 g of ethylene oxide is introducedinto the reaction mixture. The addition of the ethylene oxide requirestwo hours. The mixture is subsequently stirred as it warms to roomtemperature, is stirred for 4 hours at room temperature, and thenhydrolyzed by pouring on a mixture of 1 kg of ice and 55.0 g of ammoniumchloride. Extraction with ether, followed by conventional workup of theether solution, yield 210.0 g of 3-(2-bromo-5-(methylthio)phenyl)-1-propanol, bp, about 125°-127° (0.6mm).

C. 3-(2-Bromo-5-methylthiophenyl)propyl Bromide

To 49.0 g of the product from (A), with stirring, is added, dropwise,27.1 g of phosphorus tribromide. The mixture is stirred subsequently for3 hours at room temperature, then heated at 90°-100° for 3 hours, andthen poured into 1 kg of crushed ice. Workup via ether extraction yields52.7 g of 3-(2-bromo-5-methylthiophenyl)propyl bromide, bp. about100°-102° (0.8mm).

D. 2-Amino-1-[3-(2-bromo-5-methylthiophenyl)propyl]-pyrimidinium bromide

To a solution of 154.0 g of 3-(2-bromo-4-methylthiophenyl)propyl bromidein 400 ml of dry xylene, is added a solution of 70.0 g of2-aminopyrimidine in 300 ml of dry xylene and the mixture is heatedunder reflux for about 18 hours. The cooled xylene solution is decantedfrom the crystalline solid, the solid is triturated with 200 ml of2-propanol and filtered to give 117.0 g of crude product.Recrystallization of the latter from 2-propanol gives about 98.0 g of2-amino-1-[3-(2-bromo-4-methylthiophenyl)propyl]-pyrimidinium bromide.

E. 12,13-Dihydro-2-methylthio-11H-pyrimido[2,1-b][1,3]benzodiazocine

To a solution of 8.1 g of2-amino-1-[3-(2-bromo-5-methylthiophenyl)propyl pyrimidinium bromide in50 ml of dimethylformamide is added 10.3 g of micronized, anhydrouspotassium carbonate and 0.5 g of copper bronze. The mixture is heated at100° for about 3 hours under nitrogen while stirring, and then it isfiltered hot. The filtrate is concentrated to dryness in vacuo to giveabout 9.0 g of residue. This is extracted with two 120 ml portions ofboiling diisopropyl ether. The solution is treated with Darco, filtered,and concentrated to about 35 ml. This on cooling gives about 4.3 g of12,13-dihydro-2-methylthio-11H-pyrimido[2,1-b][1,3]benzodiazocine.

EXAMPLES 3-17

Following the procedure of example 1 (A) but substituting an equivalentamount of the substituted o-bromobenzyl alcohol in column 1 foro-bromobenzyl alcohol, there is obtained respectively, the correspondingo-bromophenethyl bromide indicated in column 2. Reaction of the latterwith 2-aminopyrimidine following the procedure of example 1 (F) yields,respectively, the pyrimidinium compound indicated in column 3. Treatingthe latter with K₂ CO₃ and copper bronze following the procedure ofexample 1 (G) yields, respectively, the final product of column 4.

    __________________________________________________________________________    Example No.                                                                          1                        2                                             __________________________________________________________________________     3.                                                                                   ##STR9##                                                                                               ##STR10##                                     4.                                                                                   ##STR11##                                                                                              ##STR12##                                     5.                                                                                   ##STR13##                                                                                              ##STR14##                                     6.                                                                                   ##STR15##                                                                                              ##STR16##                                     7.                                                                                   ##STR17##                                                                                              ##STR18##                                     8.                                                                                   ##STR19##                                                                                              ##STR20##                                     9.                                                                                   ##STR21##                                                                                              ##STR22##                                    10.                                                                                   ##STR23##                                                                                              ##STR24##                                            ##STR25##                                                                                              ##STR26##                                            ##STR27##                                                                                              ##STR28##                                            ##STR29##                                                                                              ##STR30##                                            ##STR31##                                                                                              ##STR32##                                            ##STR33##                                                                                              ##STR34##                                            ##STR35##                                                                                              ##STR36##                                            ##STR37##                                                                                              ##STR38##                                    __________________________________________________________________________    Example No.                                                                          3                        4                                             __________________________________________________________________________     3.                                                                                   ##STR39##                                                                                              ##STR40##                                     4.                                                                                   ##STR41##                                                                                              ##STR42##                                     5.                                                                                   ##STR43##                                                                                              ##STR44##                                     6.                                                                                   ##STR45##                                                                                              ##STR46##                                     7.                                                                                   ##STR47##                                                                                              ##STR48##                                     8.                                                                                   ##STR49##                                                                                              ##STR50##                                     9.                                                                                   ##STR51##                                                                                              ##STR52##                                    10.                                                                                   ##STR53##                                                                                              ##STR54##                                            ##STR55##                                                                                              ##STR56##                                            ##STR57##                                                                                              ##STR58##                                            ##STR59##                                                                                              ##STR60##                                            ##STR61##                                                                                              ##STR62##                                            ##STR63##                                                                                              ##STR64##                                            ##STR65##                                                                                              ##STR66##                                            ##STR67##                                                                                              ##STR68##                                    __________________________________________________________________________

EXAMPLES 18-30

Following the procedure of example 1, but substituting for2-aminopyrimidine an equivalent amount of the substituted2-aminopyrimidine in column 1, there is obtained, respectively, thequaternary derivative shown in column 2. Treatment of the latter asdescribed in example 1 yields, respectively, the final compoundindicated in column 3.

    __________________________________________________________________________    Example                                                                       No.  1                 2                  3                                   __________________________________________________________________________          ##STR69##                                                                                       ##STR70##                                                                                        ##STR71##                                ##STR72##                                                                                       ##STR73##                                                                                        ##STR74##                                                 +                  +                                                           ##STR75##                                                                                        ##STR76##                          20.                                                                                 ##STR77##                                                                                       ##STR78##                                                                                        ##STR79##                                ##STR80##                                                                                       ##STR81##                                                                                        ##STR82##                                ##STR83##                                                                                       ##STR84##                                                                                        ##STR85##                                ##STR86##                                                                                       ##STR87##                                                                                        ##STR88##                                ##STR89##                                                                                       ##STR90##                                                                                        ##STR91##                                ##STR92##                                                                                       ##STR93##                                                                                        ##STR94##                                ##STR95##                                                                                       ##STR96##                                                                                        ##STR97##                                                 +                  +                                                           ##STR98##                                                                                        ##STR99##                                ##STR100##                                                                                      ##STR101##                                                                                       ##STR102##                                                +                  +                                                           ##STR103##                                                                                       ##STR104##                               ##STR105##                                                                                      ##STR106##                                                                                       ##STR107##                               ##STR108##                                                                                      ##STR109##                                                                                       ##STR110##                         30.                                                                                 ##STR111##                                                                                      ##STR112##                                                                                       ##STR113##                         __________________________________________________________________________

EXAMPLE 31 11,12-Dihydropyrimido[2,1-b][1,3]benzodiazepine

To a solution of 18.0 g of 2-amino-1-(o-bromophenethyl)pyrimidiniumbromide and 14.7 g of potassium carbonate in 100 ml of n-propanol and200 ml of water is added 0.5 g of copper bronze and the mixture isheated under nitrogen, with stirring, at 90° for 2.5 hours. The mixtureis cooled and extracted with three 100 ml portions of ether, the etherextracts are washed, dried, and concentrated to give about 10.0 g ofproduct, mp about 45°-46°, after recrystallization from diisopropylether.

EXAMPLE 32 A. 1,2-Dihydro-2-imino-1-(o-bromophenethyl)pyrimidine

To a solution of 3.3 g of sodium methoxide in 120 ml of anhydrousmethanol is added 10.8 g of 2-amino-1-(o-bromophenethyl)pyirmidiniumbromide, prepared as described in example 1 (G). The solution is stirredunder nitrogen for 2 hours and then heated under reflux for 5 hours. Thesolvent is removed in vacuo and the residue is treated with 200 ml ofanhydrous ether. The ether solution is washed, dried, and concentratedin vacuo to give about 6.8 g of yellow solid. This is recrystallizedfrom hexane to give the name product, mp about 97°-98°.

B. 11,12-Dihydropyrimido[2,1-b][1,3]benzodiazepine

To a solution of 5.6 g of1,2-dihydro-2-imino-1-(o-bromophenethyl)pyrimidine in 100 ml of xyleneis added 2.8 g of potassium carbonate and 0.5 g of copper bronze and themixture is heated under reflux for 3 hours, and filtered. The filtrateis concentrated in vacuo and the residue recrystallized from diisopropylether to give about 2.3 g of the title product, mp about 45°-46°.

EXAMPLES 33-35

Following the procedure of example 1 (B) through 1 (G) but substitutingthe o-bromophenethylbromide in column I below for the o-bromobenzylbromide in part B, and substituting for 2-aminopyrimidine in part F, thecompound listed in column II, there is obtained (from part F) thepyrimidinium compound listed in column III and (from part G) thebenzodiazocine compound listed in column IV.

    __________________________________________________________________________    Example                                                                       No.   I                           II                                          __________________________________________________________________________           ##STR114##                                                                                                ##STR115##                                        ##STR116##                                                                                                ##STR117##                                        ##STR118##                                                                                                ##STR119##                                        ##STR120##                                                                                                ##STR121##                                        ##STR122##                                                                                                ##STR123##                                        ##STR124##                                                                                                ##STR125##                                 __________________________________________________________________________

EXAMPLES 36-39

Following the procedure of example 1 but substituting for2-aminopyrimidine an equivalent amount of the substituted2-aminopyrimidine in column 1, there is obtained, respectively, thequaternary derivative shown in column 2. Treatment of the latter asdescribed in example 1 yields, respectively, the final compoundindicated in column 3.

    __________________________________________________________________________    Example No.                                                                          I              II                                                      __________________________________________________________________________            ##STR126##                                                                                   ##STR127##                                                                   +                                                                              ##STR128##                                                     ##STR129##                                                                                   ##STR130##                                                                   +                                                                              ##STR131##                                                     ##STR132##                                                                                   ##STR133##                                                                   +                                                                              ##STR134##                                                     ##STR135##                                                                                   ##STR136##                                                                   +                                                                              ##STR137##                                             __________________________________________________________________________     Example No.  III                                                             __________________________________________________________________________                   ##STR138##                                                                   +                                                                              ##STR139##                                                                    ##STR140##                                                                   +                                                                              ##STR141##                                                                    ##STR142##                                                                   +                                                                              ##STR143##                                                                    ##STR144##                                                                   +                                                                              ##STR145##                                                     __________________________________________________________________________

EXAMPLES 40-51

Following the procedure of example 1 (B) through 1 (G) but substitutingfor o-bromobenzyl bromide in part B, the compound listed in column Ibelow, and substituting for 2-aminopyrimidine in part F, the compoundlisted in column II, there is obtained (from part F) the pyrimidiniumcompound listed in column III and from part G the benzodiazepinecompound listed in column IV.

    __________________________________________________________________________    Example No.                                                                          I                        II                                            __________________________________________________________________________    40.                                                                                   ##STR146##                                                                                             ##STR147##                                           ##STR148##                                                                                             ##STR149##                                           ##STR150##                                                                                             ##STR151##                                           ##STR152##                                                                                             ##STR153##                                           ##STR154##                                                                                             ##STR155##                                           ##STR156##                                                                                             ##STR157##                                           ##STR158##                                                                                             ##STR159##                                           ##STR160##                                                                                             ##STR161##                                           ##STR162##                                                                                             ##STR163##                                           ##STR164##                                                                                             ##STR165##                                   50.                                                                                   ##STR166##                                                                                             ##STR167##                                           ##STR168##                                                                                             ##STR169##                                   __________________________________________________________________________    Example No.                                                                          III                      IV                                            __________________________________________________________________________    40.                                                                                   ##STR170##                                                                                             ##STR171##                                           ##STR172##                                                                                             ##STR173##                                          +                        +                                                     ##STR174##                                                                                             ##STR175##                                           ##STR176##                                                                                             ##STR177##                                           ##STR178##                                                                                             ##STR179##                                           ##STR180##                                                                                             ##STR181##                                           ##STR182##                                                                                             ##STR183##                                           ##STR184##                                                                                             ##STR185##                                           ##STR186##                                                                                             ##STR187##                                           ##STR188##                                                                                             ##STR189##                                           ##STR190##                                                                                             ##STR191##                                   50.                                                                                   ##STR192##                                                                                             ##STR193##                                           ##STR194##                                                                                             ##STR195##                                   __________________________________________________________________________

EXAMPLE 52 Preparation of capsule formulation

    ______________________________________                                        Ingredient          Milligrams per Capsule                                    ______________________________________                                        11,12-Dihydropyrimido-                                                        [2,1-b][1,3]benzodiazepine                                                                        400                                                       Starch              80                                                        Magnesium stearate  5                                                         ______________________________________                                    

The active ingredient, starch and magnesium stearate are blendedtogether. The mixture is used to fill hard shell capsules of a suitablesize at a fill weight of 485 milligrams per capsule.

EXAMPLE 53 Preparation of tablet formulation

    ______________________________________                                        Ingredient           Milligrams per Tablet                                    ______________________________________                                        12,13-Dihydro-2-methylthio-11H-                                               pyrimido[2,1-b][1,3]benzodiazocine                                                                 300                                                      Lactose              200                                                      Corn starch (for mix)                                                                              50                                                       Corn starch (for paste)                                                                            50                                                       Magnesium stearate   6                                                        ______________________________________                                    

The active ingredient, lactose and corn starch (for mix) are blendedtogether. The corn starch (for paste) is suspended in water at a ratioof 10 grams of corn starch per 80 milliliters of water and heated withstirring to form a paste. This paste is then used to granulate the mixedpowders. The wet granules are passed through a No. 8 screen and dried at120° F. The dry granules are passed through a No. 16 screen. The mixtureis lubricated with magnesium stearate and compressed into tablets in asuitable tableting machine. Each tablet contains 300 milligrams ofactive ingredient.

EXAMPLE 54 Preparation of oral syrup formulation

    ______________________________________                                        Ingredient           Amount                                                   ______________________________________                                        11,12-Dihydropyrimido[2,1-b]-                                                 [1,3]benzodiazepine  500 mg.                                                  Sorbitol solution (70% N.F.)                                                                       40 ml.                                                   Sodium benzoate      150 mg.                                                  Sucaryl              90 mg.                                                   Saccharin            10 mg.                                                   Red Dye (F.D. & Co. No. 2)                                                                         10 mg.                                                   Cherry flavor        50 mg.                                                   Distilled water   gs. to                                                                           100 ml.                                                  ______________________________________                                    

The sorbitol solution is added to 40 milliliters of distilled water andthe active ingredient is suspended therein. The sucaryl, saccharin,sodium benzoate, flavor and dye are added and dissolved in the abovesolution. The volume is adjusted to 100 milliliters with distilledwater.

Other ingredients may replace those listed in the above formulation. Forexample, a suspending agent such as bentonite magma, tragacanth,carboxymethylcellulose, or methylcellulose may be used. Phosphates,citrates or tartrates may be added as buffers. Preservatives may includethe parabens, sorbic acid and the like and other flavors and dyes may beused in place of those listed above.

What is claimed is:
 1. A compound of the formula ##STR196## wherein m is1 or 2; when m is 1, R occupies either the 4- or 5-positions of thestarting 2-aminopyrimidine, but when R is halogen it occupies onlyposition-5; when m is 2, the two R-substituents occupy the 4- and5-positions of the starting 2-aminopyrimidine, but only one of the twoR-substituents can be halogen and it must occupy the 5-position; R isthe same or different and is hydrogen, F, Cl, Br, alkyl of from 1 to 4carbons, benzyl, phenyl, or mono-substituted phenyl wherein thesubstituent is F, Cl, Br, I, alkyl of from 1 to 4 carbons, alkoxy offrom 1 to 4 carbons, or trifluoromethyl; provided that when R ishalogen, and m is 1, R occupies only the 5-position in the starting2-aminopyrimidine; R' is hydrogen, F, Cl, Br, I, alkyl of from 1 to 4carbons, alkoxy of from 1 to 4 carbons, alkylthio of from 1 to 4carbons, alkylsulfonyl wherein the alkyl radical has from 1 to 4carbons, phenyl, phenyloxy, sulfamoyl, dialkylamidosulfonyl wherein eachalkyl radical has from 1 to 4 carbons, trifluoromethyl, mono-substitutedphenyl or mono-substituted phenyloxy wherein the substituent is F, Cl,Br, I, alkyl of from 1 to 4 carbons, alkoxy of from 1 to 4 carbons ortrifluoromethyl; n is 2 or 3 and X is Cl or Br.
 2. A compound as definedin claim 1 of the formula ##STR197## wherein R, n, and R' are as definedin claim 1 and X is Cl or Br.
 3. A compound of claim 1 having the name2-amino-1-[3-(2-bromo-5-methylthiophenyl)propyl]pyridinium bromide.
 4. Acompound of claim 1 having the name2-amino-1-(o-bromophenethyl)pyridinium bromide.